Diabetes mellitus is a metabolic disorder which afflicts a significant percentage of the human population. It is characterized by reduced carbohydrate utilization, leading to hyperglycemia, with resulting glycosuria and polyurea, giving symptoms of thirst, hunger, emaciation and finally diabetic coma. Although the short-term adverse effects of diabetes (e.g. diabetic coma) can usually be controlled by the administration of an oral hypoglycemic agent or insulin, in many cases of diabetes long-term complications develop, especially neuropathy and ocular problems such as retinopathy and cataract formation.
One approach to the control of the long-term adverse effects of diabetes is treatment with an inhibitor of the aldose reductase enzyme, with a view to blocking the reduction of glucose to sorbitol. One such aldose reductase inhibitor which is of use in controlling the chronic complications of diabetes is sorbinil, the chemical compound having the following structural formula: ##STR1## Thus, sorbinil is one of the optical antipodes of 6-fluoro-spiro[chroman-4,4'-imidazoline]-2',5'-dione. Specifically, it is the dextrorotatory isomer of 6-fluoro-spiro[chroman-4,4'-imidazolidine]-2',5'-dione, and it has the (S)-configuration at its asymmetric center based on the Cahn-Ingold-Prelog system of designating absolute configurations. (Sarges, U.S. Pat. No. 4,130,714).
A key raw material for the preparation of sorbinil is the bicyclic ketone, 6-fluoro-4-chromanone (II). In one method of producing sorbinil, 6-fluoro-4-chromanone is converted in several steps into racemic (RS)-6-fluoro-4-ureidochroman-4-carboxylic acid (III), from which the desired isomer, (S)-6-fluoro-4-ureidochroman-4-carboxylic acid (IV), is obtained by resolution with an optically active amine, and cyclized to sorbinil using glacial acetic acid. Cue and Moore, U.S. Pat. No. 4,435,578--see SCHEME I.
However, resolution of the racemic ureido-acid (III) produces, as a by-product, (R)-6-fluoro-4-ureidochroman-4-carboxylic acid (V), i.e. the isomer with the wrong stereochemistry at C-4 for cyclization to sorbinil. The (R)-ureido-acid (V) can be recovered from the resolution step, and in practice it is usually contaminated with varying amounts of the (RS)-ureido-acid (III).
Accordingly, it is an object of the present invention to provide a process for converting the (R)-ureido-acid (V), and mixtures thereof with (RS)-ureido-acid (III), back into 6-fluoro-4-chromanone by oxidation with a metal permanganate. The regenerated chromanone (II) can be reconverted into racemic ureido-acid (III) and thence to additional sorbinil. This recycling technique of (R)-ureido-acid (V) avoids economic losses and waste disposal problems in sorbinil synthesis, and thereby greatly increases overall synthesis efficiency. ##STR2##
One method for regenerating 6-fluoro-4-chromanone from (R)-ureido-acid (V), or a mixture with its racemic counterpart, has been described in U.S. Pat. No. 4,431,828. However, the process of the present invention possesses advantages over the prior regeneration process. The present process involves a single oxidation step, which is easy to carry out, operates directly on the ureido-acid, and produces the chromanone (II) in pure form. The prior art process requires a hydrolysis step prior to oxidation, and the chromanone (II) produced contains a 4-chloroimino contaminant, which has to be removed by hydrogenation.